2. Academic Validation
  3. C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

  • Cell. 2023 May 18;S0092-8674(23)00465-8. doi: 10.1016/j.cell.2023.04.031.
Jigar V Desai 1,  Dhaneshwar Kumar 2,  Tilo Freiwald 3,  Daniel Chauss 3,  Melissa D Johnson 4,  Michael S Abers 1,  Julie M Steinbrink 5,  John R Perfect 5,  Barbara Alexander 5,  Vasiliki Matzaraki 6,  Brendan D Snarr 1,  Marissa A Zarakas 1,  Vasileios Oikonomou 1,  Lakmali M Silva 7,  Raju Shivarathri 8,  Emily Beltran 9,  Luciana Negro Demontel 9,  Luopin Wang 10,  Jean K Lim 11,  Dylan Launder 12,  Heather R Conti 12,  Muthulekha Swamydas 1,  Micah T McClain 5,  Niki M Moutsopoulos 7,  Majid Kazemian 10,  Mihai G Netea 13,  Vinod Kumar 14,  Jörg Köhl 15,  Claudia Kemper 9,  Behdad Afzali 3,  Michail S Lionakis 16
Affiliations

Affiliations

  • 1 Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA.
  • 2 Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA; Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA.
  • 3 Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
  • 4 Duke Clinical Research Institute, Durham, NC, USA.
  • 5 Department of Medicine, Division of Infectious Diseases, Duke University, Durham, NC, USA.
  • 6 Department of Genetics, University of Groningen, Groningen, the Netherlands.
  • 7 Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
  • 8 Center for Discovery & Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
  • 9 Complement and Inflammation Research Section, National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA.
  • 10 Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA.
  • 11 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 12 Department of Biological Sciences, University of Toledo, Toledo, OH, USA.
  • 13 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University, Nijmegen, the Netherlands.
  • 14 Department of Genetics, University of Groningen, Groningen, the Netherlands; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University, Nijmegen, the Netherlands.
  • 15 Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
  • 16 Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, NIH, Bethesda, MD, USA. Electronic address: lionakism@mail.nih.gov.
PMID: 37220746 DOI: 10.1016/j.cell.2023.04.031
Abstract

Systemic candidiasis is a common, high-mortality, nosocomial fungal Infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in Antifungal immunity. We identified transcription of Complement System genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted Fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their Apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for Antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal Infection.

Keywords

C5; C5aR1; Candida; avacopan; candidemia; candidiasis; complement; eculizumab; kidney.

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